REFOLINON 3MG/ML SOLUTION FOR INJECTION

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FPO
Package leaflet: Information for the patient

Refolinon

®

3 mg/ml Solution for Injection
(calcium folinate)

Read all of this leaflet carefully before you start taking this medicine
because it contains important information for you.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• This medicine has been prescribed for you. Do not pass it on to others. It
may harm them, even if their symptoms are the same as yours.
• If you get any side effects talk to your doctor or nurse. This includes any
possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1.
2.
3.
4.
5.
6.

What
Refolinon is and what it is used for
What you need to know before you are given Refolinon
How Refolinon is given to you
Possible side effects
How to store Refolinon
Content of the pack and other information

1. What Refolinon is and what it is used for
Refolinon contains the active substance calcium folinate which is chemically
related to a vitamin called folic acid. Refolinon increases the levels of folic acid
in your body.
Methotrexate (a medicine used to treat cancer) can lower your body’s levels
of folic acid. Refolinon is used to reverse this and help to maintain folic acid
levels. This is known as ‘calcium folinate rescue’.
You should ask your doctor if you are unsure why you are being given
Refolinon.

2. What

you need to know before you are given Refolinon
Do not take Refolinon:
• If you are allergic (hypersensitive) to calcium folinate or any of the other
ingredients of this medicine (listed in section 6).
• If you suffer from pernicious anaemia or any anaemia’s where vitamin B12 is
deficient.
• If you are pregnant or breast-feeding your doctor will advise if you should
be given Refolinon.
Warnings and precautions
Refolinon Injection should only be given to you by intramuscular or
intravenous injection and not by any other routes of administration.
Talk to your doctor or nurse before using Refolinon.
• If you currently have, or have had any anaemias that needed treatment.
• If you are taking any other cytotoxic medicines (hydroxycarbamide,
cytarabine, mecaptopurine, thioguanine) as these can lead to macrocytosis
(enlarged red blood cells)
• If you have epilepsy and are taking phenobarbital, phenytoin, primidone,
and succinimides
• If you are taking methotrexate a medicine used in the treatment of cancer
• If you on a controlled sodium diet
Other medicines and Refolinon
Tell your doctor or pharmacist if you are taking, have recently taken, or might
take any other medicines.
Some medicines can affect the way Refolinon works, or Refolinon itself can
reduce the effectiveness of other medicines taken at the same time.

• Refolinon
can completely reduce or neutralise the effects of
cotrimoxazole, pyrimethamine when they are used together.
• Refolinon can reduce the effectiveness of drugs used to treat epilepsy
(phenobarbital, phenytoin or primidone) and lead to more frequent
seizures (fits).
• Refolinon may increase the side effects of fluorouracil (used to treat
cancer).
• The

effectiveness of Refolinon can be reduced by chloramphenicol
(an antibiotic).
Pregnancy and Breast-feeding
If you are pregnant, or breast-feeding, think you may be pregnant or are
planning to have a baby, ask your doctor or pharmacist for advice before
taking this medicine.

Driving and using machines
Refolinon is not expected to affect your ability to drive or use machines.
Refolinon contains sodium
This medicinal product contains less than 1 mmol sodium (23mg) per 30 mg
dose (10ml) i.e. essentially ‘sodium –free.’
3. How Refolinon is given to you
Your medicine will be given to you by injection under the supervision of a doctor.
The usual doses in adults and children are as follows:
Treatment of adverse drug reactions and intoxication induced by folic
acid antagonists:
Trimetrexate toxicity: Prevention: Calcium folinate should be administered
every day during treatment with trimetrexate and for 72 hours after the last
dose of trimetrexate.
Overdosage with trimetrexate: Calcium folinate should be administered for up
to 3 days every 6 hours.
Trimethoprim toxicity: After stopping trimethoprim, 3-10 mg/day calcium
folinate until recovery of a normal blood count.
Pyrimethamine toxicity: In case of high dose pyrimethamine or prolonged
treatment with low doses, calcium folinate 5 to 50 mg/day should be
simultaneously administered, based on the results of the peripheral blood counts.
Refolinon for Calcium folinate rescue:
The dose of medicine given to you will depend on your medical condition, the
dose of methotrexate you have been given and the elimination of methotrexate
from your body.

The following information is intended for medical
or healthcare professionals only:
(For further information, consult the Summary of
Product Characteristics.)

Refolinon®

3 mg/ml Solution for Injection
calcium folinate

Description
Refolinon is a solution for injection. Each ampoule of 2 ml or 10 ml solution
contains 3 mg/ml of folinic acid provided as calcium folinate. Each ampoule
also contains water for injections, sodium chloride, sodium hydroxide and
hydrochloric acid (to adjust the pH), sodium content of 0.192mmol/ampoule
and 0.96mmol/ampoule respectively.
Uses:
• To diminish the toxicity and counteract the action of folic acid
antagonists such as methotrexate in cytotoxic therapy and overdose in
adults and children. In cytotoxic therapy, this procedure is commonly
known as “Calcium Folinate Rescue”.
Warning: Calcium folinate should not be given simultaneously with a
folic acid antagonist, for the purpose of reducing or preventing clinical
toxicity, as the therapeutic effect of the antagonist may be nullified.

To reduce the harmful effects of methotrexate the first dose of calcium folinate
is 15 mg given 12 to 24 hours after methotrexate treatment starts. This is then
followed by 15 mg every 6 hours for the next 72 hours.

Posology & Method of Administration:

The level of methotrexate left in your body will be measured 48 hours after
treatment with methotrexate has started. The dose of calcium folinate given to
you may need to be adjusted.

For intravenous and intramuscular administration only. In the case of
intravenous administration, no more than 160 mg of calcium folinate should be
injected per minute due to the calcium content of the solution.

You will ﬁnd more about REFOLINON on the back of this leaﬂet

For intravenous infusion, calcium folinate may be diluted with 0.9% sodium
chloride solution or 5% glucose solution before use. Refer also to special
precautions for disposal and other handling.

FPO

Calcium folinate rescue in methotrexate therapy:
Since the calcium folinate rescue dosage regimen depends heavily on the posology
and method of the intermediate- or high-dose methotrexate administration, the
methotrexate protocol will dictate the dosage regimen of calcium folinate rescue.
Therefore, it is best to refer to the applied intermediate or high dose methotrexate
protocol for posology and method of administration of calcium folinate.
The following guidelines may serve as an illustration of regimens used in
adults, elderly and children:
Calcium folinate rescue has to be performed by parenteral administration in
patients with malabsorption syndromes or other gastrointestinal disorders
where enteral absorption is not assured. Dosages above 25-50 mg should be
given parenterally due to saturable enteral absorption of calcium folinate.
Calcium folinate rescue is necessary when methotrexate is given at doses
exceeding 500 mg/m2 body surface and should be considered with doses of
100 mg – 500 mg/m2 body surface.
Dosage and duration of calcium folinate rescue primarily depend on the type
and dosage of methotrexate therapy, the occurrence of toxicity symptoms,
and the individual excretion capacity for methotrexate. As a rule, the first dose
of calcium folinate is 15 mg (6-12 mg/m²) to be given 12-24 hours (24 hours
at the latest) after the beginning of methotrexate infusion. The same dose is
given every 6 hours throughout a period of 72 hours. After several parenteral
doses treatment can be switched over to the oral form.

dose of trimetrexate. Calcium folinate can be administered by the intravenous
route at a dose of 20 mg/m² for 5 to 10 minutes every 6 hours for a total
daily dose of 80 mg/m². Daily doses of calcium folinate should be adjusted
depending on the haematological toxicity of trimetrexate.
Overdosage (possibly occurring with trimetrexate doses above 90 mg/m2
without concomitant administration of calcium folinate): after stopping
trimetrexate, calcium folinate 40 mg/m2 IV every 6 hours for 3 days.
Trimethoprim toxicity:
After stopping trimethoprim, 3-10 mg/day calcium folinate until recovery of a
normal blood count.
Pyrimethamine toxicity:
In case of high dose pyrimethamine or prolonged treatment with low doses,
calcium folinate 5 to 50 mg/day should be simultaneously administered, based
on the results of the peripheral blood counts.
Contraindications:
• Hypersensitivity

to calcium folinate, or to any of the excipients of this
medicine.
• Pernicious

anaemia or other anaemias due to vitamin B12 deficiency.
Regarding the use of calcium folinate with methotrexate during pregnancy
and lactation, see Pregnancy and Lactation and the summaries of product
characteristics for methotrexate containing medicinal products.
Precautions

In addition to calcium folinate administration, measures to ensure the prompt
excretion of methotrexate (maintenance of high urine output and alkalinisation of
urine) are integral parts of the calcium folinate rescue treatment. Renal function
should be monitored through daily measurements of serum creatinine.

Calcium folinate should only be given by intramuscular or intravenous
injection and must not be administered intrathecally. When folinic
acid has been administered intrathecally following intrathecal overdose of
methotrexate death has been reported.

Forty-eight hours after the start of the methotrexate infusion, the residual
methotrexate-level should be measured. If the residual methotrexate-level is
>0.5 μmol/l, calcium folinate dosages should be adapted according to the
following table:

General
Calcium folinate should be used with methotrexate only under the direct supervision
of a clinician experienced in the use of cancer chemotherapeutic agents.

Many cytotoxic medicinal products – direct or indirect DNA synthesis inhibitors
– lead to macrocytosis (hydroxycarbamide, cytarabine, mecaptopurine,
thioguanine). Such macrocytosis should not be treated with folinic acid.

Additional calcium folinate to be administered
every 6 hours for 48 hours or until levels of
methotrexate are lower than 0.05 µmol/l:
15 mg/m2
100 mg/m2
200 mg/m2

Antidote to the folic acid antagonists trimetrexate, trimethoprim, and pyrimethamine:
Trimetrexate toxicity: Prevention: Calcium folinate should be administered
every day during treatment with trimetrexate and for 72 hours after the last

In epileptic patients treated with phenobarbital, phenytoin, primidone, and
succinimides there is a risk to increase the frequency of seizures due to a
decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring,
possibly monitoring of the plasma concentrations and, if necessary, dose
adaptation of the anti-epileptic drug during calcium folinate administration and
after discontinuation is recommended (see also section 4.5 Interactions).
2016‑0000571A

Calcium folinate/methotrexate
For specific details on reduction of methotrexate toxicity refer to the SPC of
methotrexate.

Concurrent administration of chloramphenicol and folic acid in folate-deficient
patients may result in antagonism of the haematopoietic response to folic acid.

Calcium folinate has no effect on non-haematological toxicities of methotrexate
such as the nephrotoxicity resulting from methotrexate and/or metabolite
precipitation in the kidney. Patients who experience delayed early methotrexate
elimination are likely to develop reversible renal failure and all toxicities
associated with methotrexate (please refer to the SPC for methotrexate).
The presence of pre-existing- or methotrexate-induced renal insufficiency is
potentially associated with delayed excretion of methotrexate and may increase
the need for higher doses or more prolonged use of calcium folinate.

Pregnancy
There are no adequate and well-controlled clinical studies conducted in
pregnant or breast-feeding women. No formal animal reproductive toxicity
studies with calcium folinate have been conducted. There are no indications
that folic acid induces harmful effects if administered during pregnancy. During
pregnancy, methotrexate should only be administered on strict indications,
where the benefits of the drug to the mother should be weighed against
possible hazards to the foetus. Should treatment with methotrexate or other
folate antagonists take place despite pregnancy or lactation, there are no
limitations as to the use of calcium folinate to diminish toxicity or counteract
the effects.

Excessive calcium folinate doses must be avoided since this might impair the
antitumor activity of methotrexate, especially in CNS tumours where calcium
folinate accumulates after repeated courses.
Resistance to methotrexate as a result of decreased membrane transport
implies also resistance to folinic acid rescue as both medicinal products share
the same transport system.
An accidental overdose with a folate antagonist, such as methotrexate, should
be treated as a medical emergency. As the time interval between methotrexate
administration and calcium folinate rescue increases, calcium folinate
effectiveness in counteracting toxicity decreases.

Pregnancy and lactation

Please refer to the SPC for methotrexate, other folate antagonists containing
medicinal products.
Lactation
It is not known whether calcium folinate is excreted into human breast
milk. Calcium folinate can be used during breast-feeding when considered
necessary according to the therapeutic indications.
Effects on ability to drive and use machines

The possibility that the patient is taking other medications that interact with
methotrexate (e.g., medications which may interfere with methotrexate
elimination or binding to serum albumin) should always be considered when
laboratory abnormalities or clinical toxicities are observed.

There is no evidence that calcium folinate has an effect on the ability to drive
or use machines.

Refolinon solution for injection contains sodium 2.2 mg/ml. To be taken into
consideration by patients on a controlled sodium diet.

When calcium folinate is given in conjunction with a folic acid antagonist (e.g.
cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may
either be reduced or completely neutralised. Therefore it should not be given
in conjunction with a folic acid antagonist.

Psychiatric disorders
Rare (≥1/10,000 to <1/1000): insomnia, agitation and depression after high doses.

Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital,
primidone, phenytoin and succinimides, and may increase the frequency of seizures
(a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be
observed because the hepatic metabolism is increased as folates are one of the
cofactors) (see also Precautions and Undesirable).

Neurological disorders
Rare (≥1/10,000 to <1/1000): increase in the frequency of attacks in epileptics
(see also Interaction with other medicaments and other forms of
interaction).

Concomitant administration of calcium folinate with 5-fluorouracil has been
shown to enhance the efficacy and toxicity of 5-fluorouracil.

General disorders and administration site conditions
Uncommon (≥1/1000 to <1/100): fever has been observed after administration
of calcium folinate as solution for injection.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product
is important. It allows continued monitoring of the benefit/risk balance of the
medicinal product. Healthcare professionals are asked to report any suspected
adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
Overdose
There have been no reported sequel in patients who have received
significantly more calcium folinate then the recommended dosage. However,
excessive amounts of calcium folinate may nullify the chemotherapeutic effect
of folic acid antagonists.
Special precautions for storage:
Store at 2°C - 8°C (in a refrigerator).
Store in original container to protect from light.
Special precautions for disposal and other handling
Prior to administration, calcium folinate should be inspected visually. The
solution for injection or infusion should be clear and yellowish solution. If
cloudy in appearance or particles are observed, the solution should be
discarded. Calcium folinate solution for injection or infusion is intended only
for single use. Any unused portion of the solution should be disposed of in
accordance with local requirements.
Package Quantities: Refolinon Injection - 10 x 2 ml ampoules, 5 x 10 ml
ampoules and 10 x 10 ml ampoules.
Not all pack sizes may be marketed
POM
PL 00057/1039
Marketing Authorisation Holder:
Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.

You will be closely monitored during the treatment. If you have any further
questions on this product, ask your doctor or pharmacist.

Store your medicine in the fridge at 2°C-8°C, store in its original container to
protect from light.

4. Possible side effects

Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer required. These
measures will help to protect the environment.

Like all medicines, this medicine can cause side effects, although not
everybody gets them.
Tell your doctor immediately if you experience any of the following
symptoms after taking this medicine. Although they are very rare, these
symptoms can be serious:
• An allergic reaction symptoms may include: rash or itching (especially
affecting the whole body), swelling of the hands, feet, ankle, face, lips or
tongue, which may cause wheezing, difficulty in breathing and swallowing.

What Refolinon contains
The active substance in Refolinon Injection is folinic acid. Each ml of solution
contains 3 mg of folinic acid as the calcium salt (calcium folinate).

Uncommon: may affect up to 1 in 100 people
• Fever after the injection

What Refolinon looks like and contents of the pack
Refolinon Injection is a sterile, clear, pale yellow liquid for injection.

Rare: may affect up to 1 in 1000 people
• sleeplessness
• agitation
• depression
• disorders affecting the intestines after high doses of Refolinon.
• increased amount of epileptic attacks if you are epileptic due to
Refolinon interacting with your epilepsy medicines.

The 2 ml ampoules are packed in a carton of 10 ampoules
The 10 ml ampoules are packed in cartons of 5 or 10 ampoules
Not all pack sizes are marketed.

If any of the side effects gets serious, or if you notice any side effects not listed
in this leaflet, please tell your doctor or pharmacist.

Date of Preparation/revision: 01/2016

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any
possible side effects not listed in this leaflet. You can also report side effects
directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. By
reporting side effects you can help provide more information on the safety of
this medicine.

Keep this medicine out of the sight and reach of children.
Refolinon should not be used after the expiry date printed on the box and on
the ampoule after EXP. The expiry date refers to the last day of the month.